Retinal or optic nerve head damage, which can result in the loss of vision, is caused by trauma and various pathological events including ischemia, hypoxia, or edema.
Retinal or optic nerve head ischemia or hypoxia results when blood supply is significantly reduced to these tissues. Ischemia is a complex pathological episode involving numerous biochemical events. In recent years, the involvement of excitatory amino acids in ischemia-related neuronal and retinal damage has been implicated. (See, e.g., Choi, Excitatory cell death, Journal of Neurobiology, volume 23, pages 1261-1276 (1992); Tung et al., A quantitative analysis of the effects of excitatory neurotoxins on retinal ganglion cells in the chick, Visual Neuroscience, volume 4, pages 217-223 (1990); Sisk et al., Histologic changes in the inner retina of albino rats following intravitreal injection of monosodium L-glutamate, Graefe's Archive for Clinical and Experimental Ophthalmology, volume 223, pages 250-258 (1985); Siliprandi et al., N-methyl-D-aspartate-induced neurotoxicity in the adult rat retina, Visual Neuroscience, volume 8, pages 567-573 (1992); and David et al., Involvement of excitatory neurotransmitters in the damage produced in chick embryo retinas by anoxia and extracellular high potassium, Experimental Eye Research, volume 46, pages 657-662 (1988).)
During ischemia or hypoxia, excitatory amino acids are markedly elevated (Benveniste et al, Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis, Journal of Neurochemistry, volume 43, pages 1369-1374 (1984)), the consequences of which may lead to excessive stimulation of post-synaptic excitatory amino acid receptors, and potentially resulting in cell injury. Antagonists against excitatory amino acid receptors have been shown to reduce neuronal and retinal damage in ischemic conditions. (See, e.g., Sheardown et al., 2,3-Dihydorxy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline: a neuroprotectant for cerebral ischemia, Science, volume 247, pages 571-574 (1990); Scatton et al., Eliprodil Hydrochloride, Drugs of the Future, volume 19, pages 905-909 (1994); and Sucher et al., N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro, Journal of Neuroscience, volume 11, pages 966-971 (1991).) Release of excitatory amino acids has been demonstrated to cause cytotoxicity due to increases in intracellular calcium levels, which in turn affects protein phosphorylation, proteolysis, lipolysis, and ultimately causing cell death. (See, e.g., Choi, Glutamate neurotoxicity and diseases of the nervous system, Neuron, volume 1, pages 623-634 (1988); Siesjo, Calcium, excitotoxins, and brain damage, NIPS, volume 5, pages 120-125 (1990) and Olney et al., The role of specific ions in glutamate neurotoxicity, Neuroscience Letters, volume 65, pages 65-71 (1986).)
Diabetic retinopathy is an ophthalmic disease leading to loss of vision and even blindness. It has been reported that glutamate excitotoxicity has played a role in such vision loss. (See, e.g., Ambati, et al., Elevated GABA, Glutamate, and VEGF in the Vitreous of Humans With Proliferative Diabetic Retinopathy, Invest. Ophthalmol. Vis. Sci., volume 38, page S771 (1997), (reported elevated levels of glutamate in vitreous samples obtained from patients with proliferative diabetic retinopathy who underwent pars plana vitrectomy. They suggested that these levels of glutamate are potentially toxic to retinal ganglion cells.); Lieth, et al., Glial Glutamate to Glutamine Conversion is Impaired in Retinas of Diabetic Rats, Invest. Ophthalmol. Vis. Sci., volume 38, page S695 (1997), (reported that glial glutamate to glutamine conversion is impaired in the retinas of diabetic rats.); and Hudson, et al., Short-Wavelength and White-on-White Automated Static Perimetry in Patients With Clinically Significant Diabetic Macular Oedema (DMO), Invest. Ophthalmol. Vis. Sci., volume 38, page S768 (1997), (reported deficits in retinal function related to ganglion cell function in patients with diabetic macular edema.)
Glutamate has also been recognized as a major excitatory neurotransmitter in the human central nervous system. It also has been demonstrated that exposure of neuronal cells to excessive levels of glutamate is neurotoxic (Knopfel et al., J. Med. Chem., volume 38, no. 9, pages 1417-1426 (1995)). Thus, conditions which can lead to excessive glutamate release (e.g., traumatic brain injury, epilepsy, Parkinson's disease, senile dementia of the Alzheimer's type, cerebral or spinal cord ischemia, etc.) can lead to neurodegeneration. Agents which block glutamate receptors during excitotoxic events may provide protection against these diseases and conditions. The excitotoxin mechanism and the potential utilities of excitatory amino acid receptor antagonists have been described in the literature (see, e.g., Olney, Drug Dev. Res., volume 17, page 299 (1988); and Meldum, Clinical Sci., volume 68, pages 113 (1985).
There are at least three ionotropic neuronal receptors that have been named for the agonist that preferentially stimulates the receptor. These receptors have been classified as: N-methyl-D-aspartate (NMDA); kainate; and AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid). These neuronal receptors are differentially distributed to specific cells in the retina. (See, generally, Massey, S., Cell types using glutamate as a neurotransmitter in the vertebrate retina, N. N. Osborne and G. J. Chader (Eds.) Progress in Retinal Research, Ch. 9, Pergammon Press: Oxford, 399-425 (1990); and Miller et al., Excitatory amino acid receptors in the vertebrate retina, in Retinal Transmitters and Modulators: Models for the Brain, (W. W. Morgan, Ed.) CRC Press, Inc., Boca Raton, II:123-160 (1985).) The localization of such receptors would account for the pathologies associated with glaucoma or inner retinal ischemia. For example, death of the retinal ganglion cell has to a large part been attributed to the NMDA receptor. (See, for example, Sucher et al., N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in retinal ganglion cells in vitro, J. Neurosci., volume 11, issue 4, pages 966-971 (1991).)
NMDA receptor antagonists have been pursued in the art for neuroprotection. For example, U.S. Pat. No. 4,690,931 (Wick et al.), U.S. Pat. No. 4,638,070 (Lembelin et al.), U.S. Pat. No. 5,306,723 (Chenard), U.S. Pat. No. 5,597,813 (Dreyer) and European Patent No. 666854 B1 disclose NMDA antagonists and methods of use. U.S. Pat. No. 5,604,244 (DeSantis) discloses intraocular irrigating solutions containing a polyamine antagonists (NMDA antagonists) and methods of use in treating retinal degeneration. None of these publications, however, disclose the novel compounds, compositions and methods of the present invention.
Given the numerous insults on a cell during ischemia and other trauma, the use of NMDA receptor antagonists alone may not provide the cytoprotective efficacy necessary to avoid necrosis. Compounds with broader inhibitory roles, i.e., compounds with dual pharmacophore efficacy may provide the added cytoprotective efficacy needed to prevent, reduce or ameliorate neuronal degradation.